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Van den Bergh, Bram; Schramke, Hannah; Michiels, Joran Elie; Kimkes, Tom E. P.; Radzikowski, Jakub Leszek; Schimpf, Johannes; Vedelaar, Silke R.; Burschel, Sabrina; Dewachter, Liselot; Lončar, Nikola; Schmidt, Alexander; Meijer, Tim; Fauvart, Maarten; Friedrich, Thorsten; Michiels, Jan; Heinemann, Matthias

Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis

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  • Media type: E-Article
  • Title: Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis
  • Contributor: Van den Bergh, Bram; Schramke, Hannah; Michiels, Joran Elie; Kimkes, Tom E. P.; Radzikowski, Jakub Leszek; Schimpf, Johannes; Vedelaar, Silke R.; Burschel, Sabrina; Dewachter, Liselot; Lončar, Nikola; Schmidt, Alexander; Meijer, Tim; Fauvart, Maarten; Friedrich, Thorsten; Michiels, Jan; Heinemann, Matthias
  • imprint: Springer Science and Business Media LLC, 2022
  • Published in: Nature Communications
  • Language: English
  • DOI: 10.1038/s41467-022-28141-x
  • ISSN: 2041-1723
  • Keywords: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>Antibiotic persistence describes the presence of phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. Perturbations of metabolic homeostasis can promote antibiotic persistence, but the precise mechanisms are not well understood. Here, we use laboratory evolution, population-wide sequencing and biochemical characterizations to identify mutations in respiratory complex I and discover how they promote persistence in <jats:italic>Escherichia coli</jats:italic>. We show that persistence-inducing perturbations of metabolic homeostasis are associated with cytoplasmic acidification. Such cytoplasmic acidification is further strengthened by compromised proton pumping in the complex I mutants. While RpoS regulon activation induces persistence in the wild type, the aggravated cytoplasmic acidification in the complex I mutants leads to increased persistence via global shutdown of protein synthesis. Thus, we propose that cytoplasmic acidification, amplified by a compromised complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters.</jats:p>
  • Access State: Open Access